Thymoma-associated Pure Red Cell Aplasia Research Articles

Clinical characteristics and prognosis of 21 patients with thymoma-associated pure red cell aplasia

Clinical characteristics and prognosis of 21 patients with thymoma-associated pure red cell aplasia

A pregnant woman with thymoma-associated pure red cell aplasia

BackgroundPure red cell aplasia (PRCA) is a hematological disorder characterized by anemia with severe reticulocytopenia caused by a marked reduction in erythroid precursors in the bone marrow. PRCA is known to be associated with pregnancy, but thymoma-associated PRCA during pregnancy is very rare, and its successful management has not been reported.Case presentationA 37-year-old primiparous woman with severe anemia was referred to our center at 27 weeks’ gestation. She was diagnosed with PRCA based on bone aspiration findings at 33 weeks’ gestation. Magnetic resonance imaging (MRI) revealed an anterior mediastinal mass 4 cm in size suspected of being thymoma. She was therefore diagnosed with thymoma-associated PRCA during pregnancy. Surgery for thymoma was planned after delivery, since the imaging findings were suggestive of early-stage thymoma (Masaoka stage I or II). With transfusion of a total 3,360 ml of red blood cells (RBCs) during pregnancy, the patient gave birth to a baby girl weighing 2,548 g at 40 weeks’ gestation. The baby showed transient congenital cutaneous candidiasis. The placental pathology revealed subamniotic inflammation with a fungal structure. Treatment with topical anti-fungal cream immediately ameliorated the baby’s skin lesion. Maternal anemia did not improve after delivery; however, the thymoma did not increase in size. At five months after delivery, the mother underwent thymectomy with oral cyclosporine A. A pathological examination revealed Masaoka stage II-a thymoma. She completely had recovered from anemia at six months after surgery. Cyclosporine A treatment was discontinued three years after surgery. Remission has been sustained for four years since surgery.ConclusionsA very rare case of thymoma-associated PRCA during pregnancy was diagnosed without any subjective symptoms and was expectantly managed, resulting in a good prognosis. Although bone marrow aspiration during pregnancy is an invasive test, it is important to confirm the diagnosis. Conservative management with blood transfusion was possible for early-stage thymoma-associated PRCA during pregnancy. Active surveys, including MRI, for PRCA during pregnancy led to the detection of thymoma at an early stage and the achievement of a preferable pregnancy outcome.

Somatic mutations in acquired pure red cell aplasia

Acquired pure red cell aplasia (PRCA) is a syndrome characterized by anemia and a marked reduction of erythroid progenitor cells with various etiologies. The 3 major subtypes of PRCA are idiopathic PRCA, large granular lymphocytic leukemia-associated PRCA and thymoma-associated PRCA, which are thought to be caused by a T-cell-mediated mechanism. In these 3 subtypes, an expansion of clonal cytotoxic T cells is often detected. In addition, those T cells recurrently harbor somatic mutations of STAT3, a gene coding one of the important signal transducers in the JAK/STAT system. Somatic mutations of clonal hematopoiesis (CH)-related genes, including epigenetic modifying genes, have also been reported, however, the data are still not mature enough upon which to draw conclusion, Somatic mutations of STAT3 and CH-related genes may be unique characteristics of acquired PRCA. However, their involvement in dyserythropoiesis or clinical relevance to the clinical course of those somatic mutations. Mutational landscapes, their involvements in dyserythropoiesis and clinical relevance in acquired PRCA remains unclear, and further investigation is needed.

Thymoma and pure red cell aplasia: A single institution experience.

e20625 Background: Thymoma is an uncommon malignancy often associated with paraneoplastic syndromes including pure red cell aplasia (PRCA), occurring in up to 5% of patients with thymoma. Considering the rarity of thymoma-associated PRCA, optimal treatment regimens and impact on thymoma disease course have yet to be established. Methods: A retrospective chart review was conducted for patients seen at the IUSCCC with thymoma and PRCA to extract and synthesize data on patient demographics, thymoma histology, hemoglobin levels, timeline of diagnoses, treatment regimens, and outcomes. Results: From 1993 to 2022, 10 patients (M:F = 4:6) with thymoma and PRCA were identified. Median follow-up duration was 75.0 months (range 32-202). Median age at thymoma diagnosis was 53.5 (range 40-80). Median age at PRCA diagnosis was 64.0 (range 40-80). Mean hemoglobin at PRCA diagnosis was 6.6. WHO classifications of thymoma included 10.0% A, 40.0% B1, 10.0% B2, 10.0% B2/B3, 30.0% not otherwise specified. Masoaka stages of thymoma included 20.0% stage I, 10.0% stage II, 10.0% stage III, 30.0% stage IVA, 30.0% stage IVB. Patients initially presented with thymoma (n = 7), PRCA (n = 1), or concurrent thymoma and PRCA (n = 2). For those initially presenting with thymoma, PRCA was subsequently diagnosed after a median 19.5 months (range 9-144). Of these 7 patients 3 experienced a relapse or progression of their thymoma at time of PRCA diagnosis, 3/7 had stable disease (1-insufficient data). Additional paraneoplastic syndromes were seen in 6 patients (hypogammaglobulinemia-2; pure white cell aplasia-1; myasthenia gravis-1; autoimmune neutropenia-1; colitis -1). Other diminished immunologic parameters observed were: immunoglobulin levels (n = 3); CD4 counts (n = 2); CD4:CD8 ratio (n = 4); and total B cell (n = 6). The primary outcome of the study was transfusion dependence, defined as requiring ≥1 PRBC transfusion per month for ≥3 months. Six achieved transfusion independence, while 3 remained transfusion dependent despite therapy (1 LTFU). Both patients with concurrent thymoma and PRCA underwent thymectomy, but only one achieved transfusion independence with additional adjuvant immunosuppressive therapies. Median duration of transfusion independence was 18.5 months (range 4-204). Median survival after bone marrow biopsy diagnosis of PRCA was 50.0 months (range 9-202). Conclusions: The impact of PRCA on thymoma disease course is variable. Most patients will recover with immunosuppressive therapy, but approximately 30.0% patients remained transfusion dependent. Our experience does not support thymectomy alone as primary treatment of PRCA. More research is needed to evaluate the mechanism of developing PRCA in thymoma and to define the optimal therapeutic approach.

T cell clonal expansion and STAT3 mutations: a characteristic feature of acquired chronic T cell-mediated pure red cell aplasia

Acquired chronic pure red cell aplasia (PRCA) develops idiopathically or in association with other medical conditions, including T cell large granular lymphocytic leukemia (T-LGLL) and thymoma. T cell dysregulation is considered a cardinal pathogenesis of PRCA, but genetic-phenotypic associations in T cell abnormalities are largely unclear. We evaluated an extended cohort of 90 patients with acquired PRCA, including 26 with idiopathic, 36 with T-LGLL-associated and 15 with thymoma-associated PRCA, for their T cell immuno-phenotypes, clonalities and STAT3 mutations. TCR repertoire skewing of CD8+ T cells was detected in 37.5% of idiopathic, 66.7% of T-LGLL-associated and 25% of thymoma-associated PRCA patients, and restriction to Vβ1 was most prominent (41%). Clonalities of TCRβ or γ chain and STAT3 mutational status were statistically associated (P = 0.0398), and they were detected in all three subtypes. The overall response rate to cyclosporin A was 73.9%, without significant difference by subtypes nor STAT3 mutational status. The T cell dysregulations, such as TCR repertoire skewing with predominant Vβ1 usage, clonality and STAT3 mutations, were frequently found across the subtypes, and the close associations between them suggest that these T cell derangements reflect a common pathophysiological mechanism among these PRCA subtypes.

Clinical and pathophysiological features of acquired pure red cell aplasia: based on the concept of T-cell dysregulations

Acquired pure red cell aplasia (PRCA) develops in a variety of contexts and thus, should be regarded as a syndrome. The three major subtypes of acquired PRCA are idiopathic PRCA, T cell large granular lymphocytic leukemia (T-LGLL)-associated PRCA, and thymoma-associated PRCA. Although the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes of the Ministry of Health, Labor and Welfare of Japan has made significant contributions to our understanding of PRCA, details of its clinical characteristics, and pathophysiological mechanisms remain largely unknown. A recent epidemiological analysis using the JSH Hematologic Disease Registry revealed that approximately 100 new cases with acquired PRCA were diagnosed annually in Japan, which was higher than previously thought to be. The median age of the patients was 73 years. A prospective observational study on chronic PRCA (PRCA2016) is currently ongoing, and it may provide new clinical insights into acquired PRCA. Dysregulation of T cells has been shown to play a central role in PRCA. We studied T cell clonalities and STAT3 mutations in 90 PRCA patients and discovered that clonal T cell expansions were frequently recognized and closely associated with STAT3 mutations in the three major types of PRCA.

Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review.

Background: Thymoma-associated haematological diseases (HDs), such as pure red cell aplasia (PRCA) and Good's syndrome, are extremely rare, and due to the paucity of large-scale studies, the characteristics, remission after thymectomy, and long-term evaluation remain undetermined.Methods: We retrospectively assessed patients with thymoma and associated HDs from Jan 2005 to Dec 2020. All patients received thymectomy and/or additional treatments for HDs. A comparison with thymoma-associated myasthenic gravis (MG), and a systematic review from PubMed/MEDLINE and Embase were conducted.Results: In the median follow-up of 56 months, 130 patients were enrolled. Patients with thymoma-associated MG (n = 46) and HDs [n = 8; PRCA (n = 5), PRCA and Good's syndrome (n = 2) and autoimmune haemolytic anaemia (n = 1)] were evaluated. Patients with MG had a significantly higher remission rate after thymectomy (50 vs. 17%; p = 0.0378) as compared to those with other autoimmune diseases. Two of seven patients with PRCA experienced remission with thymectomy alone, and an additional two patients achieved remission with thymectomy plus immunosuppressive therapy (IST). In the systematic review, 60 studies (case reports, n = 46; case series including the present study, n = 14) were evaluated. Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected.Conclusions: Our study indicates that patients with thymoma-associated autoimmune diseases other than MG have a lower remission rate than those with MG. Remission of thymoma-associated PRCA can be achieved by thymectomy and IST. This study provides insight into extremely rare but puzzling autoimmune manifestations.

Etiologies and Treatment Burden in Adult Patients with Pure Red Cell Aplasia: A Single-Center Experience and Review of Literature.

Background Pure red cell aplasia (PRCA) is less common blood disorder; the causes and the treatments of PRCA are varied. Methods We conducted a retrospective study during January 2010–December 2017, to explore the etiologies and to evaluate the response and treatment burden in adult patients with PRCA. Results Of 32 PRCA patients, median age was 57 years (18–90 years). Median hemoglobin level and reticulocyte count at the time of diagnosis were 5.6 g/dL (3.3–7.3 g/dL) and 0.3% (0.1–0.7%), respectively. Median time to hematologic recovery was 12 weeks (3–72 weeks), and median number of red blood cell transfusion (RBC) was 20 units (4–100 units). Causes of PRCA were erythropoiesis-stimulating agent (ESA) (47%), parvovirus B19 infection (19%), thymoma (13%), zidovudine (6%), primary autoimmune PRCA (6%), Kaposi's sarcoma (3%), systemic lupus erythematosus (3%), and ABO-mismatched stem cell transplantation (3%). Only 9 out of 24 treated patients achieved hematologic response within 8 weeks of treatment. Intravenous immunoglobulin therapy provided 100% response rate in patients with parvovirus B19-associated PRCA and primary autoimmune PRCA. Low response rate was found in patients receiving immunosuppressants and chemotherapy for the treatment of ESA and thymoma-associated PRCA, respectively. Conclusions Treatment outcome of PRCA depended upon the causes and the types of treatment, and the burden of RBC transfusion was very high in patients with ESA and thymoma-associated PRCA.

It Took a Village: Good's Syndrome

PRESENTATION A complex medical history became even more tangled when a 52-year-old man presented with a 4-week history of dry cough, dyspnea, weight loss, chills, subcutaneous nodules on his extremities, and fatigue. He had no fever. Initially, his primary care physician examined him and prescribed a course of clindamycin. Although the patient completed therapy, the nodules continued to progress, and they began to drain purulent material. He had been diagnosed with myasthenia gravis 7 years prior to this episode, and he was maintained on prednisone 20 mg daily and pyridostigmine. An associated thymoma had metastasized to his lung, and he had been treated with chemotherapy and radiation 2 years before this presentation. The course of his illness was further complicated by thymoma-associated pure red cell aplasia, which was successfully managed with cyclosporine.

Expansion of CD8+/perforin+ T-Cell Subset in Patients Predicts Response to Cyclosporin A Therapy in Patients with Erythroid Hypoplasia/Aplasia

Abstract 1337Erythroid hypoplasia or aplasia is a hematological condition observed in including idiopathic pure red cell aplasia (PRCA), thymoma-associated PRCA and aplastic anemia. Myelodysplastic syndrome (MDS) with erythroid hypoplasia/aplasia in bone marrow is a rare type of MDS that was not included in existing classifications of MDS. Patients with erythroid hypoplasia/aplasia have common characteristics; transfusion dependencies, immunologic abnormalities and successful immunosuppressive therapies with cyclosporin A (CsA). Thus, we may regard erythroid hypoplasia/aplasia as one of hematological disease entities. However, pathogenic mechanisms of erythroid hypoplasia/aplasia have not been fully elucidated, although T-lymphocyte-mediated inhibition of erythropoiesis is suspected to be the most possible mechanism of the pathogenesis. Recently, we reported that oligoclonal expansion of CD8+/perforin+ T cells was observed in patients with thymoma-associated PRCA and the oligoclonality was exclusively detected in CD8+ T cells, but not CD4+ T cells. To clarify the pathogenetic role of the T-cells, we analyzed the T-cell subsets and therapeutic responses in patients with erythroid hypoplasia/aplasia in bone marrow.Among 253 patients with MDS diagnosed at Hiroshima University Hospital between 2000 and June 2011, 12 patients (4.7%) showed erythroid hypoplasia/aplasia. A total of 22 patients with erythroid hypoplasia/aplasia, including 8 MDS with erythroid hypoplasia/aplasia, 3 idiopathic PRCA, 3 thymoma-associated PRCA and 8 aplastic anemia, were enrolled in this study. All patients were treated with CsA and improvement in anemia in this study followed the International Working Group (IWG) 2006 criteria. For T-cell subset analysis, mononuclear cells (MNCs) were purified from bone marrow (BM) or peripheral blood (PB) of the patients. MNCs were stained with fluorescent (FITC, PE, PerCP or APC)-conjugated antibodies for CD8, perforin, CCR7, CD62L, CD27, CD28 and CD45RO, CD45RA and were subjected to flow cytometric analysis. As controls, 30 patients with MDS without erythroid hypoplasia/aplasia and 30 patients without BM abnormalities were also analyzed.Among 22 patients with erythroid hypoplasia/aplasia, 10 patients (4 MDS with erythroid hypoplasia/aplasia, 1 idiopathic PRCA, 3 thymoma-associated PRCA and 2 aplastic anemia) responded to CsA therapy within 2 to 8 weeks. The median blood hemoglobin concentration increased from 6.5 g/dL at the baseline to 9.3 g/dL with treatment, with a median increase of hemoglobin of 2.8 g/dL from the baseline. We attempted to compare the T-cell subsets between CsA-responders and non-responders. All of 3 thymoma-associated PRCA showed good response to CsA therapy, suggesting that the oligoclonal expansion of a CD8+/perforin+ T-cell subset may be associated with the responses to immunosuppressive therapy. Thus, we focused on a T-cell subpopulation expressing CD8+/perforin+. Intriguingly, the CD8+/perforin+ T cells were significantly increased in the CsA-responders (44.3 ± 9.6%, n=10) compared to the non-responders (19.0 ± 9.3%, n=12, P<0.0001), normal BM controls (16.9 ± 7.0%, n=30) and MDS without erythroid hypoplasia/aplasia (15.1 ± 7.0%, n=30). Among the CD8+/perforin+ T cells, CD27+/CD62L+/−/CCR7low/CD28low/CD45RA++/CD45RO+ population was prominent, which is consistent with an effector memory T (TEM) cell subset described by Decrion et al.Our study reveals that CD8+/perforin+ T cell subset is a large population in the patients with CsA-responsive erythroid hypoplasia/aplasia. It is suggested that CD8+/perforin+ T cell subset may have functions to reduce erythroid progenitors via immunological mechanisms. The mechanisms may be easily suppressed by immunosuppressive therapies. In conclusion, expansion of CD8+/perforin+ T cell subset predicts response to cyclosporin A therapy in patients with erythroid hypoplasia/aplasia. The disease entity of “erythroid hypoplasia/aplasia in bone marrow with expansion of CD8+/perforin+ T cell subset”, including MDS, PRCA with or without thymoma and aplastic anemia, may have common pathogenetic mechanisms. Disclosures:No relevant conflicts of interest to declare.

Good's Syndrome-Associated Pure Red Cell Aplasia with Myelodysplastic Syndrome

We report a case of Good's syndrome-associated pure red cell aplasia (PRCA) with myelodysplastic syndrome (MDS). In this case, effector memory T (T(EM)) cells were expanded in the bone marrow. It remains uncertain whether the development of MDS was caused by the basic marrow defects or radiation therapy. However, since CD8(+) perforin(+) T(EM) cells expanded in the bone marrow, as was previously described for 3 of our patients with thymoma-associated PRCA, it is highly possible that the pathogenic mechanism of PRCA that is accompanied by thymoma is related to the expanded CD8(+) perforin(+) T(EM) cells in this MDS-complicated case.

Long-term response and outcome following immunosuppressive therapy in thymoma-associated pure red cell aplasia: a nationwide cohort study in Japan by the PRCA collaborative study group

Thymoma-associated pure red cell aplasia (PRCA) accounts for a significant proportion of cases of secondary PRCA and immunosuppressive therapy has been reported to be useful in this condition. However, because of its rarity, the long-term response and relapse rates after immunosuppressive therapy are largely unknown, and optimal management of this disorder remains unclear. The aim of this study was to collect more information on the outcome of patients with thymoma-associated PRCA. We conducted a nationwide survey in Japan. From a total of 185 patients, comprising 73 with idiopathic and 112 with secondary PRCA, 41 patients with thymoma were evaluated for this report. End-points of this study were the response rate, duration of the response after immunosuppressive therapy and overall survival. Surgical removal of thymoma was reported in 36 patients, 16 of whom developed PRCA at a median of 80 months post-thymectomy. First remission induction therapy was effective in 19 of 20 patients treated with cyclosporine, 6 of 13 patients treated with corticosteroids and 1 of 1 treated with cyclophosphamide. No cyclosporine-responders relapsed within a median observation period of 18 months (range; 1 to 118 months). Relapse of anemia was observed in three corticosteroid-responders who did not receive additional cyclosporine. Only two patients were in remission after stopping therapy for 19 and 67 months. The estimated median overall survival time of all patients was 142 months. Thymoma-associated PRCA showed an excellent response to cyclosporine and cyclosporine-containing regimens were effective in preventing relapse of anemia. It does, however, remain uncertain whether cyclosporine can induce a maintenance-free hematologic response.

Responses and Outcome of Immunosuppressive Therapy in Thymoma-Associated Pure Red Cell Aplasia: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: Secondary pure red cell aplasia (PRCA) is associated with various underlying diseases and thymoma accounts for a significant part of secondary PRCA. Thymoma-associated PRCA is generally believed to be an organ-specific autoimmune disease as well as idiopathic form, and immunosuppressive therapy including corticosteroids (CS), cyclophosphamide (CY) and cyclosporine A (CsA) have been proven useful. However, efficacy and long-term outcome of immunosuppressive therapy for secondary PRCA could be distinct among its underlying diseases. Up to the present, the overall long-term response and relapse rates after immunosuppressive therapy in thymoma-associated PRCA are largely unknown.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term relapse-free survival (RFS) and overall survival (OS) of this disorder. This report is a summary focusing on CsA therapy for thymoma-associated PRCA.Methods: The first questionnaires were sent to 109 medical centers. 273 patients were enrolled from 45 institutions. Secondary questionnaires were sent and the data on 185 patients were collected. 174 patients were eligible for further analysis and we selected 42 of 174 patients (24%) (median age, 64.5 years; range, 26 to 82 years) as thymoma-associated PRCA. Complete remission (CR), partial remission (PR) and no response (NR) were defined as the achievement of normal hemoglobin levels, the presence of anemia but with transfusion-independence and the continued presence of transfusion-dependence, respectively. RFS was estimated as transfusion-free survival without the dose escalation more than 50% of maintenance-dose. Survival was estimated by the Kaplan-Meier method and statistical difference was calculated by the generalized Wilcoxon test.Results. Surgical removal of thymoma was reported in 31 patients, and 17 patients developed PRCA after thymectomy with a median interval of 77 months (range; 1 to 366 months). Five patients underwent surgery without any immunosuppressive therapy after the diagnosis of PRCA, and no patients who achieved response were recognized. The efficacy (CR+PR) of primary treatment was seen in 19 out of 20 patients treated with CsA (95%), 6 out of 14 patients with CS (43%) and 1 of 1 with CY (100%), respectively. Relapse rates in CsA-responders and CS-responders were 0% (median observation period, 18 months) and 50% (34 months), respectively. The RFS in CsA- and CS-responders were significantly different (p=0.018). CsA-responders became independent of blood transfusion within two weeks after starting treatment. The OS did not differ substantially between the CsA- and CS-responders (p=0.663). Most CsA-responders were still on maintenance therapy, and only two patients were alive in CR after stopping therapy.Conclusion: CsA showed an excellent response in thymoma-associated PRCA. However, most patients are still receiving CsA for maintenance therapy. Therefore, other therapeutic modalities may be required to cure this disorder as is the case with idiopathic PRCA.